4-Pyrazin-2-ylmethyl-morpholine derivatives and the use thereof as medicament

ABSTRACT

and pharmaceutically acceptable salts thereof, wherein R1 and R2 are defined herein. Also disclosed are processes for their preparation, pharmaceutical compositions containing the compounds, and their use in therapy, particularly in the treatment or prevention of conditions having an association with NR2B negative allosteric modulating properties.

FIELD OF THE INVENTION

The present invention relates to novel 4-pyrazin-2-ylmethyl-morpholines,processes for their preparation, pharmaceutical compositions containingthem and their use in therapy, particularly in the treatment orprevention of conditions having an association with NR2B negativeallosteric modulating properties. The compounds of the inventionaccording to general formula A show NR2B negative allosteric modulatingproperties.

BACKGROUND OF THE INVENTION

Extensive studies over the past twenty years have indicated thatN-methyl-D-aspartate receptors (NMDA) play a relevant role inAlzheimer's disease, Parkinson's disease, dyskinesia, stroke, motorneuron disease, psychosis, epilepsy, anxiety, schizophrenia and pain.

The non-selective NMDA receptor antagonist ketamine, (racemic as well asthe S enantiomer), a medication mainly used for starting and maintaininganaesthesia, has demonstrated over the last years clinical efficacy intreating major depressive disorder (MDD) at subanaesthetic doses(Murrough et al. 2013, Am J Psychiatry. 170: 1134; Singh et al. 2016,Biol Psychiatry. 80: 424). More precisely, ketamine elicits a rapidonset of efficacy which lasts several days in MDD patientsinsufficiently responding to standard drug therapy (Berman et al. 2000.Biol Psychiatry 47:351, Serafini et al. 2014. Curr. Neuropharmacol.12:444). However, non-selective NMDA receptor antagonists have a rangeof undesirable effects which limit their application. In particulardissociative and psychogenic side effects are prominent for thenon-selective NMDA receptor antagonists such as ketamine (Krystal et al.1994. Arch. Gen. Psychiatry 51:199). In the early 1990s, it was foundthat multiple NMDA receptor subtypes exist, which contain differentNR2(A-D) subunits (Paoletti et al., 2013 Nat Rev. Neurosci 14:383). Morerecently, NR2B subtype selective NMDA receptor negative allostericmodulators (NR2B NAM) have raised interest and have shown potential in awide range of clinical indications, such as attention, emotion, mood,and pain, as well as being involved in a number of different humandisorders (Mony et. al. 2009. Br. J. Pharmacol. 157:1301; Chaffey etal., Current Anaesthesia & Critical Care 19, 183). In particular, NR2BNAM have also demonstrated antidepressant efficacy in the early stage ofclinical trials (Preskorn et al. 2008. J Clin Psychopharmacol 70:58).Preclinical studies using NR2B NAM as well as applying varioustransgenic mice strains have shown that NR2B containing NMDA-receptorsare mediating the positive effect of ketamine in e.g. the Forced SwimTest (Miller et al. 2014 eLife 3:e03581; Kiselycznyk et al. 2015, BehavBrain Res, 287:89). Furthermore, selective NR2B NAM have advantages overunselective NMDA receptor antagonists, such as ketamine, due to greatlydiminished dissociative and psychotomimetic side effects(Jimenez-Sanchez et al. 2014. Neuropsychopharmacology 39:2673). NR2B NAMdescribed to date have exhibited drawbacks with regard to their receptorpharmacology and/or to other drug properties which have limitedpotential use in human drug therapy (Taylor, et al., 2006, ClinPharmacokinet. 45: 989; Addy et al. 2009 J of Clinical Pharmacology49:856)).

WO2015/130905 discloses compounds of formula (I)

that are inhibitors of Nav1.6 useful in the treatment of multiplesclerosis, polyneuritis, multiple neuritis, amyotrophic lateralsclerosis, Alzheimer's disease or Parkinson's disease. WO2015/130905discloses the specific examples 100, 105, 106 and 107 in which ring Bcorresponds to a meta-disubstituted phenyl ring.

WO2015/130905 reports specific examples 100, 105, 106 and 107 to be weakNav1.6 inhibitors (Nay 1.6 blockage of examples 100, 105 and 107 at 1-5μM, and Nay 1.6 blockage of example 106 at >5 μM).

SUMMARY OF THE INVENTION

The present invention provides novel 4-pyrazin-2-ylmethyl-morpholines offormula A

in which

-   R¹ represents methyl, ethyl, propyl, iso-propyl, cyclopropyl,    H₃C—CH₂—CH₂—CH₂—, cyclobutyl;-   R² represents phenyl which is optionally substituted with 1, 2 or 3    substituents selected from the group consisting of fluoro, chloro,    methyl, ethyl, cyclopropyl; or a salt thereof, particularly a    pharmaceutically acceptable salt thereof.

In another embodiment, in the general formula A, R² has the same meaningas defined in any of the preceding embodiments, and

-   R¹ represents methyl, ethyl.

In another embodiment, in the general formula A, R¹ has the same meaningas defined in any of the preceding embodiments, and

-   R² represents

Compounds of the present invention are generically encompassed byformula (I) of WO2015/130905. The compounds of the present inventiondiffer structurally from the examples 100, 105, 106 and 107 explicitlydisclosed in WO2015/130905 in that they contain a para-disubstitutedpyrazinyl substructure in place of the meta-disubstituted phenyl ring.

The structural differences unexpectedly result in potent NR2B negativeallosteric modulators (see table 1), whereas the specific examples 100,105, 106 and 107 of WO2015/130905 do not show any activity on theNR1-NR2B ion channel (see table 2). Furthermore, compounds of thepresent invention do not inhibit Nay 1.6 at concentrations at whichspecific examples 100 and 105 of WO2015/130905 inhibit Nav 1.6 (5 μM;see tables 3 and 4).

Further, the compounds of the present invention show good membranepermeability and no in vitro efflux (see table 5 for MDCK assay MDR1(P-gp)). Therefore, compounds of the present invention are expected toshow a favorable brain penetration which is required for efficacious CNSmedicaments.

The MDCK assays provide information on the potential of a compound topass the blood brain barrier. Permeability measurements acrosspolarized, confluent MDCK-MDR1 cell monolayers grown on permeable filtersupports are used as an in vitro absorption model: apparent permeabilitycoefficients (PE) of the compounds across the MDCK-MDR1 cell monolayersare measured (pH 7.4, 37° C.) in apical-to-basal (AB) andbasal-to-apical (BA) transport direction. The AB permeability (PEAB)represents drug absorption from the blood into the brain and the BApermeability (PEBA) drug efflux from the brain back into the blood viaboth, passive permeability as well as active transport mechanismsmediated by efflux and uptake transporters that are expressed on theMDCK-MDR1 cells, predominantly by the overexpressed human MDR1.Identical or similar permeabilities in both transport directionsindicate passive permeation (PEBA/PEAB≤1), vectorial permeability pointsto additional active transport mechanisms. Higher PEBA than PEAB(PEBA/PEAB>5) indicates the involvement of active efflux mediated byMDR1, which might compromise the goal to achieve sufficient brainexposure. Therefore, this assay provides valuable support for selectionof compounds applicable for further in vivo testing. High permeabilitynot limited by efflux at the blood brain barrier is a favourablecharacteristic for compounds that are to be used for drugs actingprimarily in the CNS.

Further, the compounds of the present invention are metabolically stablein human liver microsomes (see table 6, metabolic stability). Therefore,compounds of the present invention are expected to have a favorable invivo clearance and thus the desired duration of action in humans.

Stability in human liver microsomes refers to the susceptibility ofcompounds to biotransformation in the context of selecting and/ordesigning drugs with favorable pharmacokinetic properties. The primarysite of metabolism for many drugs is the liver. Human liver microsomescontain the cytochrome P450s (CYPs), and thus represent a model systemfor studying drug metabolism in vitro Enhanced stability in human livermicrosomes is associated with several advantages, including increasedbioavailability and adequate half-life, which can enable lower and lessfrequent dosing of patients.

Thus, enhanced stability in human liver microsomes is a favorablecharacteristic for compounds that are to be used for drugs.

Consequently, compounds of the present invention must be more viable forhuman use.

The objective technical problem is thus to provide potent and selectiveNR2B negative allosteric modulators.

The present invention provides novel 4-pyrazin-2-ylmethyl-morpholines ofgeneral formula A that unexpectedly are potent and selective negativeallosteric modulators of NR2B.

Another aspect of the invention refers to compounds according to formulaA as potent and selective NR2B negative allosteric modulators havinghigh membrane permeability and no in vitro efflux.

Another aspect of the invention refers to compounds according to formulaA as potent and selective NR2B negative allosteric modulators havinghigh metabolic stability in human liver microsomes.

Another aspect of the invention refers to compounds according to formulaA as potent and selective NR2B negative allosteric modulators havinghigh membrane permeability, no in vitro efflux, and high metabolicstability in human liver microsomes.

Another aspect of the invention refers to pharmaceutical compositions,containing at least one compound according to formula A optionallytogether with one or more inert carriers and/or diluents.

A further aspect of the present invention refers to compounds accordingto formula A, for the use in the prevention and/or treatment ofdisorders associated with NR2B negative allosteric modulators.

Another aspect of the invention refers to processes of manufacture ofthe compounds of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows Tetracaine inhibition of Nav1.6.

FIG. 2 shows the inhibition of evoked currents in a concentration anduse dependent manner using Lidocaine as reference compound.

DETAILED DESCRIPTION OF THE INVENTION

Preparation

The following scheme shall illustrate generally how to manufacture thecompounds according to general formula A and the correspondingintermediate compounds by way of example. The abbreviated substituentsmay be as defined above if not defined otherwise within the context ofthe scheme.

Scheme 1 illustrates the synthesis of pyrazine derivatives of generalformula A. The first step is a nucleophilic substitution of asubstituted phenol derivate R2-OH and 5-chloropyrazine-2-carboxylic acidmethyl ester; the ester group is reduced to the corresponding alcoholwith NaBH₄; the hydroxy group is then converted into a leaving group(e.g. mesylate).

The last step is represented by a nucleophilic displacement employingthe mesylate and a slight excess of an amide derivative of the(S)-Morpholine-2-carboxylic acid obtained by reacting(S)-Morpholine-2-carboxylic acid methyl ester with the correspondingamine R1-NH₂.

The described synthetic approach can be used also for gram scalesynthesis applying different purification techniques such ascrystallization or column chromatography.

General Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one skilled in the art in light of thedisclosure and the context. NR2B ion channel should be understood asNMDA receptor containing the NR2B protein.

In case a compound of the present invention is depicted in form of achemical name as well as a formula, the formula shall prevail in case ofany discrepancy.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule or to the substituent to which it isbound as defined.

The term “substituted” as used herein means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's viable valencenumber is not exceeded, and that the substitution results in a stablecompound.

Stereochemistry:

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompassrotamers, tautomers and all stereo, optical and geometrical isomers(e.g. enantiomers, diastereoisomers, E/Z isomers etc.) and racematesthereof, as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereoisomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist.

Salts:

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings without excessive toxicity, irritation,allergic response, or other problem or complication, and commensuratewith a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound forms a salt or acomplex with an acid or a base.

Examples for acids forming a pharmaceutically acceptable salt with aparent compound containing a basic moiety include mineral or organicacids such as benzenesulfonic acid, benzoic acid, citric acid,ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid,hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid,methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid,salicylic acid, succinic acid, sulfuric acid or tartaric acid.

Examples for cations and bases forming a pharmaceutically acceptablesalt with a parent compound containing an acidic moiety include Na⁺, K⁺,Ca²⁺, Mg²⁺, NH₄ ⁺, L-arginine, 2,2′-iminobisethanol, L-lysine,N-methyl-D-glucamine or tris(hydroxymethyl)-aminomethane.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof. Salts of other acids than thosementioned above which for example are useful for purifying or isolatingthe compounds of the present invention (e.g. trifluoroacetate salts)also comprise a part of the invention.

BIOLOGICAL ASSAYS AND DATA List of Abbreviations

-   DMEM Dulbecco's Modified Eagle's Medium-   FBS fetal Bovine Serum-   FLIPR fluorometric imaging plate reader-   HEK293 cell line derived from human embryonic kidney cells-   HEPES hydroxyethyl-piperazineethane-sulfonic acid buffer-   IC50 half maximal inhibitory concentration-   MDCK Madin-Darby canine kidney-   MDR1 Multi drug resistance protein 1-   P-gp p-Glycoprotein-   SEM standard error mean-   EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic    acid, also known as egtazic acid

In-Vitro Effect:

Determination of In Vitro Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following in vitro NMDA NR1/NR2B cell assays:

Method:

A human HEK293 cell line with tetracyclin-inducible expression of NMDANR1/NR2B receptor was used as a test system for compound efficacy andpotency. The cell line was purchased from ChanTest, Catalog # CT6121.Compound activity was determined by measuring the effect of compounds onintracellular calcium concentration induced by glycine/glutamate agonismin a FLIPRtetra system (Molecular Devices).

Cell Culture:

The cells were obtained as frozen cells in cryo-vials and stored untiluse at −150° C. Cells were grown in culture medium (DMEM/F12, 10% FBS, 5μg/mL Blasticidin, 150 μg/mL Zeozin, 500 μg/mL Geneticin). It isimportant that density does not exceed 80% confluence. For sub-culturingthe cells were detached from flasks by Versene. For the assay, cellswere detached, washed twice with induction medium (DMEM/F12 withoutglutamine, 10% FBS, 2 μg/mL Tetracycline, 2 mM Ketamine) and seeded to384 well pure coat amine plates (Becton Dickinson, 50000 cells per wellin 50 μl) 48 h prior to assay in induction medium.

Compound Preparation

The test compounds were dissolved in 100% DMSO at a concentration of 10mM and in a first step diluted in DMSO to a concentration of 5 mM,followed by serial dilution steps in 100% DMSO. Dilution factor andnumber of dilution steps may vary according to needs. Typically 8different concentrations by 1:5 dilutions were prepared in duplicate,further intermediate dilutions (1:37.5) of the substances were carriedout with aqueous assay buffer (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂), 10mM HEPES, 10 mM Glucose, pH 7.4) resulting in a compound concentration 3times above the final test concentration and DMSO at 2.7% resulting in0.9% final DMSO concentration in the assay.

FLIPR Assay:

At the assay day cells were washed 3× with assay buffer (as describedabove), 10 μL buffer remained in the wells after washing. 10 μL Ca kitloading buffer (AAT Bioquest; prepared from the kit containing thefollowing components: Component A: Fluo-8 NW dissolved in 200 μL DMSOand 20 μl of this solution are mixed with 10 ml buffer prepared out ofcomponent B and C, Component B: 10× Pluronic® F127 Plus diluted 1:10 incomponent C, Component C: HHBS (Hanks with 20 mM Hepes) was added to thecells and the plates were incubated with lid for 60 minutes at roomtemperature. 20 μl assay buffer containing 60 μM glycine (20 μM final)and 3 μM glutamate (1 μM final) was added to column 1-23, column 24 gotassay buffer without glycine/glutamate to serve as negative unstimulatedcontrol. Fluorescence (indicating the calcium influx as a result of theNR1/NR2B ion channel activation) was read on the FLIPRtetra device for60 seconds to monitor the glutamate induced effects. After 2 minutes 20μL of compound dilution prepared as described above or controls (row1-22) in assay buffer were carefully added to the wells. Fluorescencewas read on the FLIPR tetra device for additional 6 minutes to monitorthe compound induced effects after activation by agonists. The averageof 2 measurements at 5 minutes and 5 min 10 seconds after compoundaddition is calculated and further used for IC50 calculations. Eachassay microtiter compound dilution plate contained wells (in column 23or 24) with DMSO controls instead of compound as controls forglycine/glutamate induced fluorescence (high controls) and wells with 1μM of a reference NR2B NAM as low controls (Compound 22; reference:Layton, Mark E et al, ACS Chemical Neuroscience 2011, 2(7), 352-362).

Data Evaluation and Calculation:

The output file of the reader contains the well number and measuredaverage fluorescence units. For data evaluation and calculation, themeasurement of the low control was set as 0% control and the measurementof the high control was set as 100% control. The IC50 values werecalculated using the standard 4 parameter logistic regression formula.Calculation: [y=(a−d)/(1+(x/c){circumflex over ( )}b)+d], a=low value,d=high value; x=conc M; c=IC50 M; b=slope.

NR2B negative allosteric modulators covered by general structure A andexhibiting a low IC₅₀ value are preferred.

TABLE 1 In vitro NR2B affinity of the compounds of the present inventionas obtained in the FLIPR assay Example number IC50 [nM] 1 968 2 123 3690 4 1200 5 110 6 87 7 1002 8 856 9 210 18 222 30 595 31 524 33 807 34644 35 197 36 542

TABLE 2 In vitro NR2B affinity of the closest prior art compounds(examples 100, 105, 106 and 107 in WO2015/130905) as obtained in thesame FLIPR assay as compounds in table 1 Example number in WO2015/130905IC50 [nM] 100 >8887 105 >9261 106 >9255 107 >9257

Determination of Nay 1.6. Inhibition

Equipment:

IonWorks Quattro electrophysiological platform

Compound Plate Preparation

The compounds were prepared in DMSO at 300× the final assayconcentrations of 1 and 5 μM.

The 300× DMSO stock solutions were transferred into assay plates where 2μl per well of each 300× stock solution were placed. All assay plateswere stored at −80° C. until the day of assay.

On the day of the assay, the appropriate assay plate was thawed at roomtemperature, centrifuged, and 198 μl of external recording solution wasadded and mixed thoroughly. This provided a 1:100 dilution. A further1:3 dilution occurred upon addition to the cells in the IonWorks Quattroelectrophysiological platform, giving a 1:300 dilution in total. On eachassay plate, at least 8 wells were reserved for vehicle control (0.3%DMSO) and at least 8 wells for each positive control specific to thecell line tested. The positive controls were tested at a maximalblocking and an approximate IC50 concentration. As positive controlLidocaine at concentrations of 30 and 1000 μM was used.

Electrophysiological Recording Solutions

The solutions for recording Nav1.6 currents were as follows:

External Recording Solution

NaCl 137 mM

KCl 4 mM

MgCl₂ 1 mM

CaCl₂) 1.8 mM

HEPES 10 mM

Glucose 10 mM

pH 7.3 (titrated with 10M NaOH)

Internal Recording Solution

CsF 90 mM

CsCl 45 mM

HEPES 10 mM

EGTA 10 mM

pH 7.3 (titrated with 1M CsOH)

Amphotericin B was used to obtain electrical access to the cell interiorat a final concentration of 200 μg/ml in internal recording solution.

Experimental Protocols & Data Analysis

Nav1.6 Experimental Protocol

State-dependent inhibition: Sodium channels when held at depolarizedpotential or long test pulse, the channels open and inactivate and thenstay inactivated until the membrane potential is stepped back tohyperpolarized potentials, when the inactivated channels recover frominactivation into closed state. An example is Tetracaine inhibition(FIG. 1), which is much stronger at depolarized potentials than athyperpolarized potential.

Nav1.6 Data Analysis

Cells were held at −120 mV. In order to completely inactivate the sodiumchannels (pulse 1), the cells were pulsed to +0 mV for 2500 ms andstepped back to −120 mV for 10 ms (to completely recover frominactivation, however channels that had drugs bound to them will notrecover from inactivation) before stepping to +0 mV for 20 ms (pulse 2).

IonChannel Profiler Data Filters

Data Filter Platform Criteria Seal Quality IonWorks Quattro >30 MΩ SealDrop IonWorks Quattro <50% Seal Drop (Seal Pre- Compound/Seal PostCompound) Current Amplitude IonWorks Quattro >200 pA

Assay Control Results Both the positive and vehicle control dataassociated with each cell line assayed are shown below as an example.The mean is shown for each positive and negative control as solid symbolwith the total number of individual well replicates given next to thesolid symbol. In addition, the individual data of each well are shown onthe graph as open symbols so that the variation about the mean value canbe readily assessed. These data are provided to aid in determiningwhether a compound has activities on the ion channel relative to thecontrol data and provides an indication of assay variability andaccordingly is used to judge the effect size of a compound-specificeffect that can be detected.

Shown below are the assay controls for the Nav1.6 IonWorks Quattroassay. Lidocaine, a Nav1.6 reference compound, inhibited evoked currentsin a concentration and use dependent manner as predicted (FIG. 2).

-   -   In FIG. 2, a Post/Pre value of 1.0 corresponds to 0% inhibition,        a Post/Pre value of 0.0 corresponds to 100% inhibition. To        illustrate the variation of the assay, both example 106 of        WO2015/130905 showing 14% inhibition of Nay 1.6 at 5 μM        (normalized, see table 3) and example 7 of the present invention        showing −15% inhibition of Nay 1.6 at 5 μM (normalized, see        table 4), respectively, are within the variation of the assay        when compared to assay control data, and are therefore not        showing any significant inhibition of the Nay 1.6 channel at 5        μM.

Tables 3 and 4 show the normalized percentage inhibition of Nav1.6channel. The normalized data show the compound data normalized tovehicle control (0% inhibition) and maximal inhibition control (100%inhibition); maximum inhibition at P1 by 1000 μM lidocaine (notnormalized) was ranging from 46.4% to 47.2% across the experiments. (seealso the figure Assay Control Results above).

TABLE 3 Normalized in vitro Nav 1.6 inhibition of the closest prior artcompounds (examples 100, 105, 106 and 107 in WO2015/130905) as obtainedin the same electrophysiology assay as compounds in table 4(concentrations: 1 μM and 5 μM). Normalized Normalized PercentagePercentage Example number in % inhibition % inhibition SEM SEMWO2015/130905 at 1 μM at 5 μM at 1 μM at 5 μM 100 2.2 37.8 6.2 8.4 10518.2 68 2.6 4.1 106 −0.7 14 1.6 0.4 107 −8.5 13.1 3.9 2.8

TABLE 4 Normalized in vitro Nav 1.6 inhibition of the compounds of thepresent invention as obtained in the same electrophysiology assay asprior art compounds in table 3 (concentrations: 1 μM and 5 μM).Normalized Normalized Percentage Percentage Example % inhibition %inhibition SEM SEM number at 1 μM at 5 μM at 1 μM at 5 μM 1 −9 0.5 5.53.8 2 −4.4 −4.0 3.8 4.2 3 4.6 6.8 2.5 0.9 4 3.4 5 5.0 5.1 5 −3.9 3.7 1.92.2 6 5.6 0.2 2.1 2.7 7 −9 −15 5.4 1.6 8 3 1.1 5.1 4.2 9 0 4.6 0 3.8 18−5 −10 4.3 3.7 30 −13.4 −9.4 5.3 4.6 31 −5.8 −7 3.6 1.2 33 −10.5 −6.64.6 1.0

NR2B negative allosteric modulators covered by general structure A whichare not showing any significant Nav1.6 inhibition are preferred.

The compounds of the present invention do not show any significantinhibition of the Nay 1.6 channel at 1 and 5 μM, respectively (see table4 and Assay Control Results), whereas examples 100 and 105 ofWO2015/130905 show 37.8% and 68% inhibition of Nav 1.6 at 5 μM,respectively (see table 3). Examples 106 and 107 of WO2015/130905 do notshow any significant inhibition of the Nay 1.6 channel at 1 and 5 μM,respectively (i.e. inhibition is within assay variability, see table 3and Assay Control Results).

MDCK Assay P-Gp

Apparent permeability coefficients (Papp) of the compounds across theMDCK-MDR1 monolayers (MDCKII cells transfected with human MDR1 cDNAexpression plasmid) are measured in apical-to-basal (AB) andbasal-to-apical (BA) direction.

MDCK-MDR1 cells (6×10⁵ cells/cm²) are seeded on filter inserts (Corning,Transwell, polycarbonate, 0.4 μm pore size) and cultured for 9 to 10days. Compounds dissolved in DMSO stock solution (1-20 mM) are dilutedwith HTP-4 aqueous buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO₄, 1.8mM CaCl₂, 4.17 mM NaHCO₃, 1.19 mM Na₂HPO₄, 0.41 mM NaH₂PO₄, 15 mM HEPES,20 mM glucose, pH 7.4) supplemented with 0.25% BSA to prepare thetransport solutions (final concentration: 1 or 10 μM, final DMSO<=0.5%).The transport solution is applied to the apical or basolateral donorside for measuring A-B or B-A permeability, respectively. The receiverside contains HTP-4 buffer supplemented with 0.25% BSA. Samples arecollected at the start and end of experiment from the donor and atvarious time intervals for up to 2 hours also from the receiver side forconcentration measurement by HPLC-MS/MS (RapidFire High-throughput MSSystem (Agilent) coupled to QTrap 6500 (AB Sciex) or TSQ Vantage (ThermoScientific)). Sampled receiver volumes are replaced with fresh receiversolution. Efflux ratio is calculated dividing the Papp (b-a) values bythe Papp (a-b) values. Results are shown in Table 5.

TABLE 5 Papp (a − b) mean efflux ratio Ex. [10−6 cm/s] PEBA/PEAB 1 590.7 2 76 0.6 3 75 0.7 4 61 0.7 5 59 0.8 6 71 0.8 7 66 0.7 8 70 0.6 9 620.9 18 61 0.8 30 81 0.4 31 66 0.6 33 59 0.7

The experimental results above show that compounds of the presentinvention are potent NR2B NAMs having high membrane permeability and noin vitro efflux anticipating excellent capability to cross the bloodbrain barrier.

Metabolic Stability

The metabolic degradation of the test compound was assayed at 37° C.with pooled human liver microsomes. The final incubation volume of 60 μlper time point contains TRIS buffer pH 7.6 at room temperature (0.1 M),magnesium chloride (5 mM aqueous solution), microsomal protein (1 mg/mLfor human) and the test compound at a final concentration of 1 μM.Following a short preincubation period at 37° C., the reactions wereinitiated by addition of betanicotinamide adenine dinucleotidephosphate, reduced form (NADPH, 1 mM), and terminated by transferring analiquot into acetonitril after different time points. Aftercentrifugation (10000 g, 5 min), an aliquot of the supernatant wasassayed by HPLC-MS/MS as described above for the MDCK assay P-gp for theamount of parent compound. The half-life was determined by the slope ofthe semi-logarithmic plot of the concentration-time profile. Results areshown in table 6.

TABLE 6 Half-life − t½ [min] Ex. human liver microsomes 1 >130 2 >1303 >130 4 >130 5 >130 6 >130 7 >130 8 >130 9 >130 18 >130 30 >130 31 >13033 >130

The experimental results above show that compounds of the presentinvention are potent NR2B NAMs having high stability in human livermicrosomes.

The present invention provides compounds according to formula A thatunexpectedly result in a favorable combination of the following keyparameters:

-   -   1) potent and selective negative allosteric modulation of NR2B,    -   2) high stability in human liver microsomes, and    -   3) high permeability and no in vitro efflux at MDCK-MDR1 cell        transporters.

Pharmaceutical Composition

Suitable preparations for administering the compounds of the presentinvention will be apparent to those with ordinary skill in the art andinclude for example tablets, pills, capsules, suppositories, lozenges,troches, solutions, syrups, elixirs, sachets, injectables, inhalatives,powders, etc. The content of the pharmaceutically active compound(s) mayvary in the range from 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-% ofthe composition as a whole.

Suitable tablets may be obtained, for example, by mixing a compound ofthe present invention with known excipients, for example inert diluents,carriers, disintegrants, adjuvants, surfactants, binders and/orlubricants and pressing the resulting mixture to form tablets.

Use in Treatment/Method of Use

Human therapeutic applications of NR2B NAM have been summarized inreviews by Traynelis et al. (Traynelis et al., Pharmacology Reviews,2010, 62:405), Beinat et al. (Beinat et al., Current MedicinalChemistry, 2010, 17:4166) and Mony et al. (Mony et al., British J.Pharmacology, 2009, 157:1301).

The present invention relates to compounds which are useful in thetreatment of psychiatric disorders, diseases and conditions whereinnegative allosteric modulation of NR2B is of therapeutic benefit,including: (1) mood disorders and mood affective disorders; (2)schizophrenia spectrum disorders; (3) neurotic, stress-related andsomatoform disorders including anxiety disorders; (4) disorders ofpsychological development; (5) behavioral syndromes associated withphysiological disturbances and physical factors; (6) substance-relatedand addictive disorders; (7) disease associated with symptoms ofnegative and positive valence; (8) pain; (9) cerebrovascular diseases;(10) episodic and paroxysmal disorders; (11) neurodegenerative diseases.

In view of their pharmacological effect, compounds of the presentinvention are suitable for use in the treatment of a disorder, diseaseor condition selected from the list consisting of

(1) treatment of mood disorders and mood affective disorders includingbipolar disorder I depressed, hypomanic, manic and mixed form; bipolardisorder II; depressive disorders, such as single depressive episode orrecurrent major depressive disorder, minor depressive disorder,depressive disorder with postpartum onset, depressive disorders withpsychotic symptoms; major depressive disorder with or withoutconcomitant anxious distress, mixed features, melancholic features,atypical features, mood-congruent psychotic features, mood-incongruentpsychotic features, catatonia.

(2) treatment of mood disorders belonging to the schizophrenia spectrumand other psychotic disorders including schizophrenia andschizoaffective disorder with associated negative and cognitivesymptoms.

(3) treatment of disorders belonging to the neurotic, stress-related andsomatoform disorders including anxiety disorders, general anxietydisorder, panic disorder with or without agoraphobia, specific phobia,social phobia, chronic anxiety disorders; obsessive compulsive disorder;reaction to sever stress and adjustment disorders, such aspost-traumatic stress disorder; other neurotic disorders such asdepersonalisation-derealisation syndrome.

(4) treatment of disorders of psychological development includingpervasive developmental disorders, including Asperger's syndrome andRett's syndrome, autistic disorders, childhood autism and overactivedisorder associated with mental retardation and stereotyped movements,specific developmental disorder of motor function, specificdevelopmental disorders of scholastic skills, attentiondeficit/hyperactivity disorder.

(5) treatment of behavioral syndromes associated with physiologicaldisturbances and physical factors including mental and behaviouraldisorders associated with the puerperium, including postnatal andpostpartum depression; eating disorders, including anorexia nervosa andbulimia nervosa and other impulse control disorders.

(6) treatment of disorders of substance-related and addicitivedisorders, which are substance use disorders induced by alcohol,cannabis, hallucinogen, stimulant, hypnotic, tobacco.

(7) treatment of disease associated with symptoms of negative andpositive valence including anhedonia, sustained threat and loss,suicidal ideation.

(8) treatment of acute and chronic pain which is related to neuropathy,e.g. diabetic neuropathy or polyneuropathy, physiological processes andphysical disorders including e.g. low back pain, pain in the joints,disease of the musculoskeletal system and connective tissue, e.g.rheumatism, myalgia, nerve, nerve root and plexus disorders, e.g.phantom limb syndrome with pain, carpal tunnel syndrome.

(9) treatment of cerebrovascular diseases, e.g. intracerebral orsubararchnoid haemorrhage, cerbral infarction, stroke, occlusion andstenosis, cerebral atherosclerosis, cerebral amyloid angiopathy.

(10) treatment of episodic and paroxymal disorders, e.g. epilepsy.

(11) treatment of diseases which include forms of neurodegeneration,e.g. stroke, Alzheimer's disease and Huntingon's disease.

As used herein, unless otherwise noted, the terms “treating”,“treatment” shall include the management and care of a human subject orhuman patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentinvention to prevent the onset of the symptoms or complications,alleviate the symptoms or complications, or eliminate the disease,condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

According to another aspect, the present invention provides a compoundof formula A or a pharmaceutically acceptable salt thereof for use inthe treatment and/or prevention of the above mentioned conditions.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is used in addition to behaviouraltherapy, TMS (transcranial magnetic stimulation), ECT (electroconvulsivetherapy) and other therapies.

Combination Therapy

Compounds according to the present invention can be combined with othertreatment options known to be used in the art in connection with atreatment of any of the indications the treatment of which is in thefocus of the present invention.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is administered in addition totreatment with one or more antidepressant selected from the listconsisting of duloxetine, escitalopram, bupropion, venlafaxine,desvenlafaxine, sertraline, paroxetine, fluoxetine, vortioxetine,mirtazapine, citalopram, vilazodone, trazodone, amitriptyline,clomipramine, agomelatine, levomilnacipran, lithium, doxepin,nortriptyline. The term “antidepressant” shall mean any pharmaceuticalagent or drug which can be used to treat depression or diseasesassocaited with depressive symptoms. According to another aspect, thepresent invention provides a compound of formula A according to any oneof the preceding aspects characterized in that the compound of formula Ais administered in addition to treatment with one or more antipsychoticselected from the list consisting of aripiprazole, paliperidonepalmitate, lurasidone, quetiapine, risperidone, olanzapine,paliperidone, brexpiprazole, clozapine, asenapine, chlorpromazine,haloperidol, cariprazine, ziprasidone, amisulpride, iloperidone,fluphenazine, blonanserin, aripiprazole lauroxil. The term“antipsychotic” shall mean any pharmaceutical agent or drug which can beused to treat diseases associated with psychotic or depressive symptoms.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is administered in addition totreatment with one or more psychostimulant selected from the listconsisting of lisdexamfetamine, methylphenidate, amfetamine,dexamfetamine, dexmethylphenidate, armodafinil, modafinil. The term“psychostimulant” shall mean any pharmaceutical agent or drug which canbe used to treat diseases like mood disorders, or impulse controldisorders.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is administered in addition totreatment with nootropics selected from the list consisting ofoxiracetam, piracetam, or the natural product St John's-wort.

According to another aspect, the present invention provides a compoundof formula A which is administered in addition to treatment with one ormore antidepressant, antipsychotic, psychostimulant, nootropics ornatural product according to any one of the preceding aspectscharacterized in that the combination of compound of formula A and oneor more antidepressant, antipsychotic, psychostimulant, nootropics ornatural product is used in addition to behavioural therapy, TMS(transcranial magnetic stimulation), ECT (electroconvulsive therapy) andother therapies.

EXPERIMENTAL SECTION Abbreviations

-   ACN acetonitrile-   APCI Atmospheric pressure chemical ionization-   Boc tert-butyloxycarbonyl-   CDI 1,1′-carbonyldiimidazole-   CO₂ Carbon Dioxide-   D day-   DA Diode Array-   DCM dichloromethane-   DIPE diisopropylether-   DIPEA diisopropylethylamine-   DMF dimethylformamide-   e.e. enantiomeric excess-   ESI electrospray ionization (in MS)-   EtOAc ethylacetate-   EtOH ethanol-   Ex. example-   h hour(s)-   HATU    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HPLC high performance liquid chromatography-   HPLC-MS coupled high performance liquid chromatography-mass    spectrometry-   M molar (mol/L)-   MeOH methanol-   min minute(s)-   MS mass spectrometry-   MW molecular weight-   NH3 ammonia-   PSI Pound per square inch-   rt room temperature-   R_(t) retention time-   scCO2 supercritical CO2-   solv solvent-   TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin-layer chromatography-   SFC Supercritical fluid chromatography

Abbreviations within Spectral Data

-   1H-NMR Proton nuclear magnetic resonance-   br broad-   δ chemical shift-   d doublet-   dd doublet of doublets-   dt doublet of triplets-   DMSO-d₆ hexa-deutero-dimethylsulfoxide-   H proton-   Hz Hertz (=1/second)-   J coupling constant-   m multiplet-   ppm parts per million-   q quartet-   s singlet-   t triplet-   td triplet of doublets

General Analytics.

All reactions were carried out using commercial grade reagents andsolvents. NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHzinstrument using TopSpin 3.2 p16 software. Chemical shifts are given inparts per million (ppm) downfield from internal referencetrimethylsilane in 6 units. Selected data are reported in the followingmanner: chemical shift, multiplicity, coupling constants (J),integration. Analytical thin-layer chromatography (TLC) was carried outusing Merck silica gel 60 F254 plates. All compounds were visualized assingle spots using short wave UV light. Low resolution mass spectra wereobtained using a liquid chromatography mass spectrometer (LCMS) thatconsisted of an Agilent 1100 series LC coupled to a Agilent 6130quadrupole mass spectrometer (electrospray positive ionization).

Methods:

HPLC-Ms Methods:

Method 1

Method Name: Z003_S05 Device description: Agilent 1200 with DA- andMS-Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer:Waters Description: Gradient/ % Sol % Sol Back Solvent Time [Water[Aceto- Flow Temp pressure [min] 0.1% NH₃] nitrile] [ml/min] [° C.][PSI] 0.0 95.0 5.0 2.2 60.0 0.2 95.0 5.0 2.2 60.0 1.2 0.0 100.0 2.2 60.01.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Method 2

Method Name: Z011_S03 Device description: Agilent 1200 with DA- andMS-Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer:Waters Description: Method Name: Z011_S03 Gradient/ % Sol % Sol BackSolvent Time [Water [Aceto- Flow Temp pressure [min] 0.1% NH₃] nitrile][ml/min] [° C.] [PSI] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.20.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Method 3

Method Name: Z017_S04 Device description: Agilent 1200 with DA- andMS-Detector Column: Sunfire C18_3.0 × 30 mm_1.8 μm Column producer:Waters Description: Gradient/ % Sol % Sol Back Solvent Time [Water[Aceto- Flow Temp pressure [min] 0.1% TFA] nitrile] [ml/min] [° C.][PSI] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.01.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Chiral SFC Analytical Methods:

Method 4: I_SA_20_IPA_NH₃_001

Method Name: I_SA_20_IPA_NH₃ _(—) 001 Device description: Agilent 1260SFC with DAD and MS Column: CHIRAL ART ® Amylose SA_4.6 × 250 mm_5 μmColumn producer: YMC Gradient/ % Sol Back Solvent Time % Sol [ETOH 20Flow Temp pressure [min] [scCO2] mM NH₃] [ml/min] [° C.] [PSI] 0.0 85.015.0 4.0 40.0 2175.0 10.0 85.0 15.0 4.0 40.0 2175.0

Method 5: I_IC_30_IPA_NH₃_001

Method Name: I_IC_30_IPA_NH₃ _(—) 001 Device description: Agilent 1260SFC with DAD and MS Column: Chiralpak ® IC_4.6 × 250 mm_5 μm Columnproducer: Daicel Gradient/ % Sol Back Solvent Time % Sol [MEOH 20 FlowTemp pressure [min] [scCO2] mM NH₃] [ml/min] [° C.] [PSI] 0.0 70.0 30.04.0 40.0 2175.0 10.0 7.0 30.0 4.0 40.0 2175.0

Preparative HPLC Conditions for Purification:

Instrument: (Agilent 1100). Eluents: Water-NH₄OH 5% solution inWater-CH₃CN;

Flow: 50 ml/min; Temperature 60° C.; Column: XBridge C18.

PREPARATION OF INTERMEDIATES Example 1a

(S)-Morpholine-2-carboxylic acid methyl ester hydrochloride (35 g; 192.7mmol) was mixed together with 400 ml of a 8M solution of Methylamine inEtOH. The reaction mixture was stirred at room temperature over 60hours. The solvent was removed under reduced pressure, THF (500 ml) andTEA (50 ml) were added and the reaction mixture stirred at roomtemperature during 12 hours. A precipitate was formed; the suspensionwas filtered via a glass filter and the filtrate solution was evaporatedunder reduced pressure. Obtained 23.5 g of the desired product as solid.

Example 1a: Analytical Data

Chiral SFC Method: I_IC_30_IPA_NH₃_001. M Rt [min]: 3.72; e.e. 100%

MS: 145 (M+H)⁺

Example 1b

(S)-Morpholine-2-carboxylic acid methyl ester hydrochloride (5 g; 27.5mmol) was mixed together with 138 ml of a 2M solution of Ethylamine inTHF. The reaction mixture was stirred at room temperature over 60 hours.The solvent was removed under reduced pressure, THF (500 ml) and TEA (50ml) were added and the reaction mixture stirred at room temperatureduring 12 hours. A precipitate was formed; the suspension was filteredvia a glass filter and the filtrate solution was evaporated underreduced pressure. Obtained 4.3 g of the desired product as solid.

Example 1b

Chiral SFC Method: I_IC_30_IPA_NH₃_001. M Rt [min]: 3.23; e.e. >99%

MS: 159 (M+H)⁺

Example 2a

5-Chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol) and4-Fluoro-phenol (0.78 g; 6.95 mmol) were dissolved in DMSO (10 ml);K₂CO₃ (1.2 g; 8.69 mmol) was added and the reaction mixture was stirred45 min at 60° C. The reaction mixture was poured into water (50 ml) andstirred 15 minutes. The obtained precipitate was washed with water, a10% aqueous solution of K₂CO₃ and dried. Obtained 1.4 g of solid.

Example 2a

HPLC-MS; Method: Z011_S03; R_(t) [min]: 0.92 MS: 249 (M+H)⁺

Example 2b

Example 2b was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 2-Fluoro-4-methyl phenol (0.75 ml; 6.95 mmol). Obtained1.5 g of the desired compound as a solid.

Example 2b

HPLC-MS; Method: Z011_S03; R_(t) [min]: 0.99 MS: 263 (M+H)⁺

Example 2c

Example 2c was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 4-methyl phenol (0.73 ml; 6.95 mmol). Obtained 1.35 g ofthe desired compound as a solid.

Example 2c

HPLC-MS; Method: Z011_S03; R_(t) [min]: 0.97 MS: 245 (M+H)⁺

Example 2d

Example 2d was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 2,4-dimethyl phenol (0.83 ml; 6.95 mmol). Obtained 1.45 gof the desired compound as a solid.

Example 2d

HPLC-MS (Method): Z018_S04; R_(t) [min]: 1.05 MS: 259 (M+H)⁺

Example 2e

Example 2e was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 4-chloro-2-Fluoro-phenol (0.74 ml; 6.95 mmol). Obtained1.55 g of the desired compound as a solid.

Example 2e

HPLC-MS (Z011_S03): R_(t) [min]: 1.01

MS: 283 and 285 (M+H)⁺; Isotopic pattern for 1 Cl observed

Example 2f

Example 2f was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 2,4-difluoro phenol (0.67 ml; 6.95 mmol). Obtained 1.50 gof the desired compound as a solid.

Example 2f

HPLC-MS (Z011_S03): R_(t) [min]: 0.95 MS: 267 (M+H)⁺

Example 2g

Example 2g was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 4-chloro-phenol (0.89 g; 6.95 mmol). Obtained 1.5 g ofthe desired compound as a solid.

Example 2g

HPLC-MS (Z011_S03): R_(t) [min]: 0.99

MS: 265 and 267 (M+H)+; Isotopic pattern for 1 Cl observed

Example 2h

Example 2h was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 4-fluoro-2-methyl phenol (0.88 g; 6.95 mmol). Obtained1.5 g of the desired compound as a solid.

Example 2h

HPLC-MS (Z011_S03): R_(t) [min]: 0.97 MS: 263 (M+H)⁺

Example 2i

Example 2i was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 2-fluoro phenol (0.62 ml; 6.95 mmol). Obtained 1.22 g ofthe desired compound as a solid.

Example 2i

HPLC-MS (Z011_S03): R_(t) [min]: 0.92 MS: 249 (M+H)⁺

Example 2k

Example 2k was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester (1g; 5.79 mmol), 2-chloro phenol (0.71 ml; 6.95 mmol). Obtained 1.51 g ofthe desired compound as a solid.

Example 2k

HPLC-MS (Z011_S03): R_(t) [min]: 0.97

MS: 265 and 267 (M+H)⁺; Isotopic pattern for 1 Cl observed

Example 2j

Example 2j was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester(1.00 g; 5.80 mmol), Phenol (0.65 g; 6.95 mmol). Obtained 1.30 g of thedesired compound as a solid.

Example 2j

HPLC-MS (Z017_S04): R_(t) [min]: 0.92 MS: 231 (M+H)⁺

Example 2l

Example 2l was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester(1.00 g; 5.80 mmol), 2.6-Difluorophenol (0.90 g; 6.95 mmol). Obtained1.52 g of the desired compound as a solid.

Example 2l

HPLC-MS (Z017_S04): R_(t) [min]: 0.97 MS: 267 (M+H)⁺

Example 2m

Example 2m was synthesised in analogy to Example 2a.

Starting materials: 5-Chloro-pyrazine-2-carboxylic acid methyl ester(320 mg; 1.85 mmol), 2-fluoro-6-methyl-phenol (257 mg; 2.04 mmol).Obtained 480 mg of the desired compound as a solid.

Example 2m

HPLC-MS (Z017_S04): R_(t) [min]: 1.00 MS: 263 (M+H)⁺

Example 3a

Example 2a (1.4 g; 5.64 mmol) was dissolved in MeOH (15 ml); NaBH₄ (0.64g; 16.9 mmol) was added and the reaction mixture stirred 3 hours at roomtemperature. Water was added to quench the reaction; the reactionmixture was then evaporated under reduced pressure and the residuepartitioned between EtOAc (100 ml) and a 10% aqueous solution of K₂CO₃(30 ml). The organic phase was dried over Na₂SO₄ and the residueobtained after evaporation of the solvents purified by flashchromatography (Eluent: gradient starting with Petrol Ether/EtOAc 3/1 toPetrol Ether/EtOAc 2/1). Obtained 0.8 g of the desired compound (oil).

Example 3a

HPLC-MS (Z011_S03): R_(t) [min]: 0.80 MS: 221 (M+H)⁺

Example 3b

Example 3b was prepared in analogy to Example 3a. Starting materials:Example 2b (1.5 g; 5.72 mmol). Obtained 1 g of the desired compound.

Example 3b

HPLC-MS; Method: Z011_S03; R_(t) [min]: 0.88 MS: 235 (M+H)⁺

Example 3c

Example 3c was prepared in analogy to Example 3a. Starting materials:Example 2c (1.35 g; 5.53 mmol). Obtained 0.95 g of the desired compound.

Example 3c

HPLC-MS (Z011_S03): R_(t) [min]: 0.86 MS: 217 (M+H)⁺

Example 3d

Example 3d was prepared in analogy to Example 3a. Starting materials:Example 2d (1.45 g; 5.61 mmol). Obtained 0.83 g of the desired compound.

Example 3d

HPLC-MS (Z011_S03): R_(t) [min]: 0.91 MS: 231 (M+H)⁺

Example 3e

Example 3e was prepared in analogy to Example 3a. Starting materials:Example 2e (1.55 g; 5.48 mmol). Obtained 1.02 g of the desired compound.

Example 3e

HPLC-MS (Method): Z011_S03 R_(t) [min]: 0.91

MS: 255 and 257 (M+H)⁺; Isotopic pattern for 1 Cl observed

Example 3f

Example 3f was prepared in analogy to Example 3a. Starting materials:Example 2f (1.50 g; 5.64 mmol). Obtained 1.04 g of the desired compound.

Example 3f

HPLC-MS (Method): Z011_S03 R_(t) [min]: 0.83 MS: 239 (M+H)⁺

Example 3g

Example 3g was prepared in analogy to Example 3a. Starting materials:Example 2g (1.5 g; 5.67 mmol). Obtained 0.83 g of the desired compound.

Example 3g

HPLC-MS (Method): Z011_S03 R_(t) [min]: 0.88

MS: 237 and 239 (M+H)⁺; Isotopic pattern for 1 Cl observed

Example 3h

Example 3h was prepared in analogy to Example 3a. Starting materials:Example 2h (1.5 g; 5.72 mmol). Obtained 0.86 g of the desired compound.

Example 3h

HPLC-MS (Method): Z011_S03 R_(t) [min]: 0.86 MS: 235 (M+H)⁺

Example 3i

Example 3i was prepared in analogy to Example 3a. Starting materials:Example 2i (1.22 g; 4.92 mmol). Obtained 0.75 g of the desired compound.

Example 3i

HPLC-MS (Method): Z011_S03 R_(t) [min]: 0.8 MS: 221 (M+H)⁺

Example 3k

Example 3k was prepared in analogy to Example 3a. Starting materials:Example 2k (1.51 g; 5.71 mmol). Obtained 0.85 g of the desired compound.

Example 3k

HPLC-MS (Method): Z011_S03 R_(t) [min]: 0.85

MS: 237 and 239 (M+H)⁺; Isotopic pattern for 1 Cl observed

Example 3j

Example 3j was prepared in analogy to Example 3a. Starting materials:Example 2k (1.30 g; 5.65 mmol). The crude obtained after evaporation ofthe organic solvents was used as such in the next steps. Obtained 0.98 gof the desired compound (content 70%).

Example 3j

HPLC-MS (Method): Z017_S03 R_(t) [min]: 0.79 MS: 203 (M+H)⁺

Example 3l

Example 3l was prepared in analogy to Example 3a. Starting materials:Example 2l (1.52 g; 5.71 mmol). The crude obtained after evaporation ofthe organic solvents was used as such in the next steps. Obtained 1.30 gof the desired compound (content 85%).

Example 3l

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.84 MS: 238 (M*)+

Example 3m

Example 3m was prepared in analogy to Example 3a. Starting materials:Example 2m (480 mg; 1.83 mmol). The crude product after evaporation ofthe organic solvents was used as such in the next steps. Obtained 420 mgof the desired compound (content 85%).

Example 3m

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.87 MS: 235 (M+H)⁺

Example 4a

Example 3a (0.8 g; 3.63 mmol) was dissolved in 2-methyl-THF (Aldrich)(40 ml); TEA (0.76 ml; 5.45 mmol) was added dropwise, followed byMethansulphonyl Chloride (0.3 ml; 4 mmol). The mixture was stirred 1.5hours at rt before being worked up. A 5% NaHCO₃ solution in water wasadded to reaction mixture, the phases were separated and dried overNa₂SO₄. The crude obtained after evaporation of the organic solvents wasused as such in the next steps. Obtained 1.05 g of the desired product.

Example 4a

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.93 MS: 299 (M+H)⁺

Example 4b

Example 4b was prepared in analogy to example 4a. Starting material:Example 3b (1 g; 4.27 mmol). Obtained 1.3 g. The product was used assuch in the next step.

Example 4b

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.99 MS: 313 (M+H)⁺

Example 4c

Example 4c was prepared in analogy to example 4a. Starting material:Example 3c (0.95 g; 4.39 mmol). Obtained 1.25 g. The product obtainedafter work up was used as such in the next step.

Example 4c

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.98 MS: 295 (M+H)⁺

Example 4d

Example 4d was prepared in analogy to example 4a. Starting material:Example 3d (0.83 g; 3.61 mmol). Obtained 1.1 g. The product obtainedafter work was used as such in the next step.

Example 4d

HPLC-MS (Method): Z017_S04 R_(t) [min]: 1.02 MS: 309 (M+H)⁺

Example 4e

Example 4e was prepared in analogy to example 4a. Starting material:Example 3e (1.02 g; 4.0 mmol). Obtained 1.32 g. The product obtainedafter work was used as such in the next step.

Example 4e

HPLC-MS (Method): Z017_S04 R_(t) [min]: 1.01 MS: 333 and 335 (M+H)+;Isotopic pattern for 1 Cl observed

Example 4f

Example 4f was prepared in analogy to example 4a. Starting material:Example 3f (1.04 g; 4.37 mmol). Obtained 1.35 g. The product obtainedafter work was used as such in the next step.

Example 4f

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.95 MS: 317 (M+H)⁺

Example 4g

Example 4g was prepared in analogy to example 4a. Starting material:Example 3g (0.83 g; 3.51 mmol). Obtained 1.1 g. The product obtainedafter work was used as such in the next step.

Example 4g

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.99 MS: 315 and 317 (M+H)+;Isotopic pattern for 1 Cl observed

Example 4h

Example 4h was prepared in analogy to example 4a. Starting material:Example 3h (0.86 g; 3.67 mmol). Obtained 1.12 g. The product obtainedafter work was used as such in the next step.

Example 4h

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.97 MS: 313 (M+H)⁺

Example 4i

Example 4i was prepared in analogy to example 4a. Starting material:Example 3i (0.75 g; 3.41 mmol). Obtained 1.0 g. The product obtainedafter work was used as such in the next step.

Example 4i

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.93 MS: 299 (M+H)⁺

Example 4k

Example 4k was prepared in analogy to example 4a. Starting material:Example 3k (0.85 g; 3.59 mmol). Obtained 1.1 g. The product obtainedafter work was used as such in the next step.

Example 4k

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.97

MS: 315 and 317 (M+H)⁺; Isotopic pattern for 1 Cl observed

Example 4j

Example 4j was prepared in analogy to example 4a. Starting material:Example 3k (0.98 g; content 70%; 3.39 mmol). The product obtained afterwork up was used as such in the next step. Obtained 1.35 g of thedesired product (content 70%).

Example 4j

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.91 MS: 281 (M+H)⁺

Example 4l

Example 4l was prepared in analogy to example 4a. Starting material:Example 3l (1.30 g; content 85%; 4.64 mmol). The product obtained afterwork up was used as such in the next step. Obtained 1.70 g (content85%).

Example 4l

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.95 MS: 317 (M+H)⁺

Example 4m

Example 4m was prepared in analogy to example 4a. Starting material:Example 3m (0.42 g; content 85%; 1.52 mmol). Obtained 0.55 g. Theproduct obtained after work up was used as such in the next step.

Example 4m

HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.98 MS: 313 (M+H)⁺

EXEMPLARY EMBODIMENTS Example 1

Example 4a (100 mg; 0.34 mmol) and Example 1a (53.17 mg; 0.37 mmol) weredissolved in THF (5 ml); pyridine (0.08 ml; 1 mmol) was added and thereaction mixture heated at 50° C. during 5 hours. The reaction mixturewas cooled to rt, diluted with MeOH (3 ml) and filtered via a syringefilter. The obtained solution was purified by preparative HPLC. Obtained53 mg of the desired compound.

Example 1

HPLC-MS; Method: Z011_S03; R_(t) [min]: 0.87 MS: 347 (M+H)⁺

Chiral SFC; Method: I_SA_20_IPA_NH₃_001 Rt [min]: 2.00; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.02 (m, 1H); 2.17-2.24 (m, 1H); 2.58(m, 3H); 2.66-2.71 (m, 1H); 2.95 (m, 1H); 3.54-3.69 (m, 3H); 3.83-3.90(m, 2H); 7.27 (m, 4H); 7.67 (m, 1H); 8.19 (m, 1H); 8.47 (m, 1H).

Example 2

Example 2 was synthesised in analogy to example 1.

Starting materials: Example 4b (100 mg; 0.32 mmol)+Example 1a (50.78 mg;0.35 mmol). The crude was purified by preparative HPLC. Obtained 105 mgof the desired compound.

Example 2

HPLC-MS: Method: Z011_S03; R_(t) [min]: 0.93 MS: 361 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 Rt [min]; 1.96; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.02 (m, 1H); 2.16-2.24 (m, 1H);2.32-2.36 (m, 3H); 2.57 (m, 3H); 2.65-2.70 (m, 1H); 2.94 (m, 1H);3.54-3.69 (m, 3H); 3.83-3.90 (m, 2H); 7.07 (m, 1H); 7.21 (m, 1H); 7.26(m, 1H); 7.67 (m, 1H); 8.17 (m, 1H); 8.55 (m, 1H).

Example 3

Example 3 was synthesised in analogy to example 1.

Starting materials: Example 4c (100 mg; 0.34 mmol)+Example 1a (53.9 mg;0.37 mmol). The crude was purified by preparative HPLC. Obtained 80 mgof the desired compound.

Example 3

HPLC-MS: Method: Z011_S03; R_(t) [min]: 0.91 MS; 343 (M+H)⁺

Chiral SFC; Method: I_SA_20_IPA_NH₃_001 Rt [min]: 2.34; e.e. 99.59%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.02 (m, 1H); 2.16-2.24 (m, 1H);2.30-2.34 (m, 3H); 2.57 (m, 3H); 2.68 (m, 1H); 2.95 (m, 1H); 3.54-3.68(m, 3H); 3.83-3.90 (m, 2H); 7.06-7.10 (m, 2H); 7.23 (m, 2H); 7.63-7.70(m, 1H); 8.18 (m, 1H); 8.43 (m, 1H).

Example 4

Example 4 was synthesised in analogy to example 1.

Starting materials: Example 4d (100 mg; 0.32 mmol)+Example 1a (51.4 mg;0.36 mmol). The crude was purified by preparative HPLC. Obtained 55 mgof the desired compound.

Example 4

HPLC-MS Z003_S05: R_(t) [min]: 1.14 MS: 357 (M+H)⁺

Chiral SFC; Method: I_SA_20_IPA_NH₃_001 Rt [min]: 2.07; e.e. 94%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.99-2.07 (m, 4H); 2.15-2.24 (m, 1H);2.26-2.32 (m, 3H); 2.57 (m, 3H); 2.68 (m, 1H); 2.94 (m, 1H); 3.54-3.67(m, 3H); 3.83-3.89 (m, 2H); 6.97-7.06 (m, 2H); 7.11-7.14 (m, 1H); 7.67(m, 1H); 8.13-8.16 (m, 1H); 8.44 (m, 1H).

Example 5

Example 5 was synthesised in analogy to example 1.

Starting materials: Example 4e (100 mg; 0.30 mmol)+Example 1a (47.66 mg;0.33 mmol). The crude was purified by preparative HPLC. Obtained 70 mgof the desired compound.

Example 5

HPLC-MS Z011_S03: R_(t) [min]: 10.96 MS: 381 and 383 (M+H)⁺; Isotopicpattern for 1 Cl observed

Chiral SFC; Method: I_SA_20_IPA_NH₃_001 Rt [min]: 2.27; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.03 (m, 1H); 2.21 (m, 1H); 2.57 (m,3H); 2.65-2.70 (m, 1H); 2.94 (m, 1H); 3.54-3.70 (m, 3H); 3.83-3.90 (m,2H); 7.37 (m, 1H); 7.47 (m, 1H); 7.63-7.69 (m, 2H); 8.20 (d, J=1.31 Hz,1H); 8.61 (d, J=1.33 Hz, 1H).

Example 6

Example 6 was synthesised in analogy to example 1.

Starting materials: Example 4f (100 mg; 0.32 mmol)+Example 1a (50.14 mg;0.35 mmol). The crude was purified by preparative HPLC. Obtained 81 mgof the desired compound.

Example 6

HPLC-MS: Method: Z003_505; R_(t) [min]: 1.05 MS: 365 (M+H)⁺

Chiral SFC; Method: I_SA_20_IPA_NH₃_001 Rt [min]: 1.67; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.99-2.07 (m, 1H); 2.20 (m, 1H); 2.57(m, 3H); 2.64-2.72 (m, 1H); 2.94 (m, 1H); 3.54-3.71 (m, 3H); 3.83-3.90(m, 2H); 7.14-7.20 (m, 1H); 7.44-7.52 (m, 2H); 7.63-7.72 (m, 1H); 8.19(d, J=1.37 Hz, 1H); 8.60 (d, J=1.35 Hz, 1H).

Example 7

Example 7 was synthesised in analogy to example 1.

Starting materials: Example 4g (100 mg; 0.32 mmol)+Example 1a (50.39 mg;0.35 mmol). The crude was purified by preparative HPLC. Obtained 97 mgof the desired compound.

Example 7

HPLC-MS (Method): Z011_503; R_(t) [min]: 0.93; MS: 363 and 365 (M+H)+;Isotopic pattern for 1 Cl observed

Chiral SFC; Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 2.95; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.02 (m, 1H) 2.21 (m, 1H) 2.57 (m, 3H)2.65-2.74 (m, 1H) 2.96 (m, 1H) 3.54-3.70 (m, 3H) 3.83-3.91 (m, 2H)7.24-7.29 (m, 2H) 7.47-7.51 (m, 2H) 7.68 (m, 1H) 8.21 (d, J=1.35 Hz, 1H)8.50 (d, J=1.35 Hz, 1H)

Example 8

Example 8 was synthesised in analogy to example 1.

Starting materials: Example 4h (100 mg; 0.32 mmol)+Example 1a (50.78 mg;0.35 mmol). The crude was purified by preparative HPLC. Obtained 60 mgof the desired compound.

Example 8

HPLC-MS (Method): Z003_S05; R_(t) [min]: 1.09 MS: 361 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 1.79 e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.99-2.06 (m, 1H); 2.08-2.10 (m, 3H);2.16-2.25 (m, 1H); 2.57 (d, J=4.74 Hz, 3H); 2.65-2.71 (m, 1H); 2.95 (m,1H); 3.54-3.68 (m, 3H); 3.83-3.90 (m, 2H); 7.05-7.10 (m, 1H); 7.16-7.22(m, 2H); 7.64-7.70 (m, 1H); 8.16 (d, J=1.33 Hz, 1H); 8.49 (d, J=1.32 Hz,1H).

Example 9

Example 9 was synthesised in analogy to example 1.

Starting materials: Example 4i (100 mg; 0.34 mmol)+Example 1a (53.17 mg;0.37 mmol). The crude was purified by preparative HPLC. Obtained 49 mgof the desired compound.

Example 9

HPLC-MS (Method): Z003_S05; R_(t) [min]: 1.03 MS: 347 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 1.84; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.02 (m, 1H); 2.20 (m, 1H); 2.56-2.59(m, 3H); 2.65-2.70 (m, 1H); 2.94 (m, 1H); 3.54-3.70 (m, 3H); 3.83-3.90(m, 2H); 7.25-7.43 (m, 4H); 7.64-7.69 (m, 1H); 8.19 (m, 1H); 8.59 (m,1H).

Example 18

Example 18 was synthesised in analogy to example 1.

Starting materials: Example 4k (100 mg; 0.32 mmol)+Example 1a (50.78 mg;0.35 mmol). The crude was purified by preparative HPLC. Obtained 64 mgof the desired compound.

Example 18

HPLC-MS Method: Z003_S05; R_(t) [min]: 1.07 MS: 363 and 365 (M+H)+;Isotopic pattern for 1 Cl observed Chiral SFC Method:I_SA_20_IPA_NH₃_001 R_(t) [min]: 2.38; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.02 (m, 1H); 2.21 (m, 1H); 2.57-2.58(m, 3H); 2.64-2.71 (m, 1H); 2.95 (m, 1H); 3.54-3.70 (m, 3H); 3.83-3.90(m, 2H); 7.30-7.36 (m, 1H); 7.38-7.46 (m, 2H); 7.59-7.63 (m, 1H);7.63-7.70 (m, 1H); 8.18 (d, J=1.33 Hz, 1H); 8.57 (d, J=1.34 Hz, 1H).

Example 30

Example 30 was synthesised in analogy to example 1.

Starting materials: Example 4f (100 mg; 0.32 mmol) and Example 1b (60mg; 0.38 mmol). The crude was purified via preparative HPLC. Obtained 58mg.

Example 30

HPLC-MS; Method: Z003_S05; R_(t) [min]: 1.10 MS: 379 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 1.55; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 0.98 (t, J=7.18 Hz, 3H); 2.02 (m, 1H);2.21 (m, 1H); 2.65-2.70 (m, 1H); 2.93 (m, 1H); 3.04-3.11 (m, 2H);3.54-3.62 (m, 1H); 3.64-3.68 (m, 2H); 3.84-3.88 (m, 2H); 7.14-7.20 (m,1H); 7.44-7.52 (m, 2H); 7.69 (m, 1H); 8.19 (br s, 1H); 8.60 (m, 1H).

Example 3l

Example 3l was synthesised in analogy to example 1.

Starting materials: Example 4b (100 mg; 0.32 mmol) and Example 1b (60mg; 0.38 mmol). The crude was purified via preparative HPLC. Obtained 57mg.

Example 3l

HPLC-MS; Method: Z011_S03; R_(t) [min]: 0.98 MS: 375 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 1.83; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 0.99 (t, J=7.16 Hz, 3H); 2.02 (t,J=10.77 Hz, 1H); 2.21 (m, 1H); 2.32-2.36 (m, 3H); 2.67 (m, 1H); 2.93 (m,1H); 3.08 (m, 2H); 3.54-3.69 (m, 3H); 3.83-3.89 (m, 2H); 7.07 (m, 1H);7.21 (m, 1H); 7.26 (t, J=8.17 Hz, 1H); 7.69 (m, 1H); 8.17 (m, 1H); 8.55(m, 1H).

Example 33

Example 33 was synthesised in analogy to example 1.

Starting materials: Example 4k (100 mg; 0.32 mmol) and Example 1b (60mg; 0.38 mmol). The crude was purified via preparative HPLC. Obtained 37mg.

Example 33

HPLC-MS; Method: Z003_S05; R_(t) [min]: 0.96 MS: 377 and 379 (M+H)₊:isotopic pattern for 1 Cl observed

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 2.16; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 0.99 (t, J=7.18 Hz, 3H); 2.02 (t,J=10.76 Hz, 1H); 2.21 (td, J=11.31, 3.19 Hz, 1H); 2.65-2.71 (m, 1H);2.94 (m, 1H); 3.04-3.11 (m, 2H); 3.54-3.70 (m, 3H); 3.83-3.89 (m, 2H);7.30-7.46 (m, 3H); 7.61 (dd, J=7.96, 1.44 Hz, 1H); 7.69 (m, 1H); 8.18(d, J=1.33 Hz, 1H); 8.57 (d, J=1.32 Hz, 1H).

Example 34

Example 34 was synthesised in analogy to example 1.

Starting materials: Example 4j (100 mg; content 70%; 0.25 mmol) andExample 1a (39.6 mg; 0.28 mmol). The crude was purified via preparativeHPLC. Obtained 71.0 mg of the desired product.

Example 34

HPLC-MS; Method: Z011_S03; R_(t) [min]: 0.85 MS: 329 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 2.29; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.03 (m, 1H); 2.21 (m, 1H); 2.58 (m,3H); 2.69 (m, 1H); 2.96 (m, 1H); 3.54-3.69 (m, 3H); 3.83-3.91 (m, 2H);7.18-7.28 (m, 3H); 7.44 (m, 2H); 7.63-7.71 (m, 1H); 8.20 (d, J=1.37 Hz,1H); 8.46 (d, J=1.35 Hz, 1H).

Example 35

Example 35 was synthesised in analogy to example 1.

Starting materials: Example 4l (130 mg; 0.35 mmol) and Example 1a (55.4mg; 0.38 mmol). The crude was purified via preparative HPLC. Obtained71.0 mg of the desired product.

Example 35

HPLC-MS; Method: Z003_505; R_(t) [min]: 1.06 MS: 365 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 1.63; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.04 (m, 1H); 2.21 (m, 1H); 2.57 (m,3H); 2.63-2.71 (m, 1H); 2.94 (m, 1H); 3.57 (m, 1H); 3.68 (s, 2H);3.82-3.91 (m, 2H); 7.28-7.44 (m, 3H); 7.60-7.74 (m, 1H); 8.21 (d, J=1.37Hz, 1H); 8.71 (d, J=1.35 Hz, 1H).

Example 36

Example 36 was synthesised in analogy to example 1.

Starting materials: Example 4m (130 mg; 0.42 mmol) and Example 1a (66.0mg; 0.46 mmol). The crude was purified via preparative HPLC. Obtained87.0 mg of the desired product.

Example 36

HPLC-MS; Method: Z011_503; R_(t) [min]: 0.92 MS: 361 (M+H)⁺

Chiral SFC Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 1.71; e.e. 100%

¹H NMR (400 MHz, DMSO-d₆); δ ppm: 2.03 (m, 1H); 2.15-2.22 (m, 4H); 2.57(m, 3H); 2.62-2.75 (m, 1H); 2.95 (m, 1H); 3.52-3.61 (m, 1H); 3.66 (s,2H); 3.80-3.93 (m, 2H); 7.12-7.27 (m, 3H); 7.62-7.74 (m, 1H); 8.16 (d,J=1.38 Hz, 1H); 8.62 (d, J=1.35 Hz, 1H).

What is claimed is:
 1. A compound of formula A

or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, cyclopropyl, H₃C—CH₂—CH₂—CH₂—, and cyclobutyl; R² is phenyl which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, methyl, ethyl, and cyclopropyl.
 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl or ethyl; R² is selected from the group consisting of


3. The (S)-enantiomer according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: Ex.  1

 2

 3

 4

 5

 6

 7

 8

 9

18

30

31

33

34

35

36


4. A pharmaceutically acceptable salt of a compound according to claim
 1. 5. A method for treating and/or preventing bipolar disorder I depressed, hypomanic, manic and mixed form, bipolar disorder II, depressive disorders, major depressive disorder with or without concomitant anxious distress, mixed features, melancholic features, atypical features, mood-congruent psychotic features, mood-incongruent psychotic features, or catatonia, the method comprising administering a pharmaceutically effective amount of a compound of formula A according to claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
 6. A method for treating and/or preventing single depressive episode or recurrent major depressive disorder, minor depressive disorder, depressive disorder with postpartum onset, or depressive disorders with psychotic symptoms, the method comprising administering a pharmaceutically effective amount of a compound of formula A according to claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
 7. The method according to claim 5, wherein the compound of formula A, or a pharmaceutically acceptable salt thereof, is administered with another antidepressant drug.
 8. The method according to claim 5, wherein the patient is further being treated with behavioural therapy.
 9. The method according to claim 6, wherein the compound of formula A, or a pharmaceutically acceptable salt thereof, is administered with another antidepressant drug.
 10. The method according to claim 6, wherein the patient is further being treated with behavioural therapy.
 11. A pharmaceutical composition comprising the compound according to claim 1, or a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent and/or carrier. 